Conformational dynamics of the human serotonin transporter during substrate and drug binding

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Conformational dynamics of the human serotonin transporter during substrate and drug binding. / Möller, Ingvar R; Slivacka, Marika; Nielsen, Anne Kathrine; Rasmussen, Søren G F; Gether, Ulrik; Loland, Claus J; Rand, Kasper D.

In: Nature Communications, Vol. 10, No. 1, 1687, 11.04.2019.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Möller, IR, Slivacka, M, Nielsen, AK, Rasmussen, SGF, Gether, U, Loland, CJ & Rand, KD 2019, 'Conformational dynamics of the human serotonin transporter during substrate and drug binding', Nature Communications, vol. 10, no. 1, 1687. https://doi.org/10.1038/s41467-019-09675-z

APA

Möller, I. R., Slivacka, M., Nielsen, A. K., Rasmussen, S. G. F., Gether, U., Loland, C. J., & Rand, K. D. (2019). Conformational dynamics of the human serotonin transporter during substrate and drug binding. Nature Communications, 10(1), [1687]. https://doi.org/10.1038/s41467-019-09675-z

Vancouver

Möller IR, Slivacka M, Nielsen AK, Rasmussen SGF, Gether U, Loland CJ et al. Conformational dynamics of the human serotonin transporter during substrate and drug binding. Nature Communications. 2019 Apr 11;10(1). 1687. https://doi.org/10.1038/s41467-019-09675-z

Author

Möller, Ingvar R ; Slivacka, Marika ; Nielsen, Anne Kathrine ; Rasmussen, Søren G F ; Gether, Ulrik ; Loland, Claus J ; Rand, Kasper D. / Conformational dynamics of the human serotonin transporter during substrate and drug binding. In: Nature Communications. 2019 ; Vol. 10, No. 1.

Bibtex

@article{93c018ccf9b44ed3994613c2d8f8c6fb,
title = "Conformational dynamics of the human serotonin transporter during substrate and drug binding",
abstract = "The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.",
author = "M{\"o}ller, {Ingvar R} and Marika Slivacka and Nielsen, {Anne Kathrine} and Rasmussen, {S{\o}ren G F} and Ulrik Gether and Loland, {Claus J} and Rand, {Kasper D}",
year = "2019",
month = apr,
day = "11",
doi = "10.1038/s41467-019-09675-z",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Conformational dynamics of the human serotonin transporter during substrate and drug binding

AU - Möller, Ingvar R

AU - Slivacka, Marika

AU - Nielsen, Anne Kathrine

AU - Rasmussen, Søren G F

AU - Gether, Ulrik

AU - Loland, Claus J

AU - Rand, Kasper D

PY - 2019/4/11

Y1 - 2019/4/11

N2 - The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.

AB - The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.

U2 - 10.1038/s41467-019-09675-z

DO - 10.1038/s41467-019-09675-z

M3 - Journal article

C2 - 30976000

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1687

ER -

ID: 216654538